Biomarker de-Mendelization: principles, potentials and limitations of a strategy to improve biomarker prediction by reducing the component of variance explained by genotype [article]

Alisa D Kjaergaard, Stig E Bojesen, Børge G Nordestgaard, Julia S Johansen, George Davey Smith
2018 bioRxiv   pre-print
AbstractIn observational studies, the Mendelian randomization approach can be used to circumvent confounding, bias and reverse causation, and to assess a potential causal association between a biomarker and risk of disease. If, on the other hand, a substantial component of variance of a non-causal biomarker is explained by genotype, then genotype could potentially attenuate the observational association and the strength of the prediction. In order to reduce the component of variance explained
more » ... ariance explained by genotype, an approach that can be seen as the inverse of Mendelian randomization - biomarker de-Mendelization - appears plausible.Plasma YKL-40 is a good candidate for demonstrating principles of biomarker de-Mendelization because it is a non-causal biomarker with a substantial component of variance explained by genotype. This approach is an attempt to improve the observational association and the strength of a predictive biomarker; it is explicitly not aimed at detection of causal effects.We studied 21 161 individuals form the Danish general population with measurements of YKL-40 concentration and rs4950928 genotype. Four different methods for biomarker de-Mendelization are explored for alcoholic liver cirrhosis and lung cancer.De-Mendelization methods only improved predictive ability slighly. We observed an interaction between genotype and markers of developing disease with respect to YKL-40 concentration.Even when genotype explains 14% of the variance in a non-causal biomarker, we found no useful empirical improvement in risk prediction by biomarker de-Mendelization. This could reflect the predictive interaction between genotype and disease development being removed which counterbalanced any beneficial properties of the method in this situation.
doi:10.1101/428276 fatcat:6cyinr6porhgrot6gonfdq7bpa